Aprepitant

Antiemetic / Nausea

Also known as: Emend, Fosaprepitant, Cinvanti, MK-0869

NK1 Receptor AntagonistsResearch phase: FDA-approvedRegulatory: FDA-approved (2003) for prevention of chemotherapy-induced and postoperative nausea/vomiting (Emend). IV formulation fosaprepitant (Emend IV) also approved.

Mechanism

Aprepitant is an oral drug that blocks the NK1 receptor (the target of Substance P) to prevent chemotherapy-induced nausea and vomiting. It works on the brain's vomiting center where Substance P triggers nausea. It is used in combination with other anti-nausea drugs (5-HT3 antagonists and dexamethasone) as part of triple antiemetic therapy for highly emetogenic chemotherapy.

Technical detail

Aprepitant is a non-peptide, selective NK1 receptor (TACR1) antagonist. It crosses the blood-brain barrier to block substance P binding at NK1R in the nucleus tractus solitarius (NTS) and area postrema — key emetic centers. NK1R blockade prevents Gq-PLC-IP3 signaling that mediates the delayed phase of chemotherapy-induced emesis. Fosaprepitant is the IV phosphorylated prodrug rapidly converted to aprepitant by phosphatases. Aprepitant is a moderate CYP3A4 inhibitor and CYP2C9 inducer, necessitating dose adjustments with concurrent medications (notably dexamethasone and warfarin).

Evidence

Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial.
Schmitt T et al. (2014) — Journal of Clinical Oncology — PMID: 25225424
Phase III RCT in 362 myeloma patients undergoing high-dose melphalan/ASCT found aprepitant improved complete response for CINV versus placebo (58% vs 41%), increased freedom from major nausea and emesis, and improved FLIE quality-of-life scores.
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